Aldactazide

CLINICAL PHARMACOLOGY

Mechanism Of Action

ALDACTAZIDE is a combination of
two diuretic agents with different but complementary mechanisms and sites of
action, thereby providing additive diuretic and antihypertensive effects.
Additionally, the spironolactone component helps to minimize the potassium loss
characteristically induced by the thiazide component.

The diuretic effect of
spironolactone is mediated through its action as a specific pharmacologic
antagonist of aldosterone, primarily by competitive binding of receptors at the
aldosterone-dependent sodium-potassium exchange site in the distal convoluted
renal tubule. Hydrochlorothiazide promotes the excretion of sodium and water
primarily by inhibiting their reabsorption in the cortical diluting segment of
the distal renal tubule.

ALDACTAZIDE is effective in
significantly lowering the systolic and diastolic blood pressure in many
patients with essential hypertension, even when aldosterone secretion is within
normal limits.

Both spironolactone and
hydrochlorothiazide reduce exchangeable sodium, plasma volume, body weight, and
blood pressure. The diuretic and antihypertensive effects of the individual
components are potentiated when spironolactone and hydrochlorothiazide are
given concurrently.

Pharmacokinetics

Spironolactone is rapidly and
extensively metabolized. Sulfur-containing products are the predominant
metabolites and are thought to be primarily responsible, together with
spironolactone, for the therapeutic effects of the drug. The following
pharmacokinetic data were obtained from 12 healthy volunteers following the
administration of 100 mg of spironolactone (ALDACTONE film-coated tablets)
daily for 15 days. On the 15th day, spironolactone was given immediately after
a lowfat breakfast and blood was drawn thereafter.

Accumulation Factor: AUC (0–24 hr, day 15)/AUC (0–24 hr, day 1)

Mean Peak Serum Concentration

Mean (SD) Post-Steady State Half-Life

7-α-(thiomethyl) spirolactone (TMS)

1.25 at 3.2 hr

391 ng/mL (terminal)

13.8 hr (6.4)

6-β-hydroxy-7-α (thiomethyl) spirolactone (HTMS)

1.5 at 5.1 hr

125 ng/mL (terminal)

15.0 hr (4.0)

Canrenone (C)

1.41 (terminal)

181 ng/mL at 4.3 hr

16.5 hr (6.3)

Spironolactone (β half-life)

1.3 1.4 hr (0.5)

80 ng/mL at 2.6 hr

Approximately

The pharmacological activity of
spironolactone metabolites in man is not known. However, in the
adrenalectomized rat the antimineralocorticoid activities of the metabolites C,
TMS, and HTMS, relative to spironolactone, were 1.10, 1.28, and 0.32,
respectively. Relative to spironolactone, their binding affinities to the
aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06,
respectively.

In humans, the potencies of TMS
and 7-α-thiospirolactone in reversing the effects of the synthetic
mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33
and 0.26, respectively, relative to spironolactone. However, since the serum
concentrations of these steroids were not determined, their incomplete
absorption and/or first-pass metabolism could not be ruled out as a reason for
their reduced in vivo activities.

Spironolactone and its
metabolites are more than 90% bound to plasma proteins. The metabolites are
excreted primarily in the urine and secondarily in bile.

The effect of food on
spironolactone absorption (two 100 mg ALDACTONE tablets) was assessed in a
single dose study of 9 healthy, drug-free volunteers. Food increased the
bioavailability of unmetabolized spironolactone by almost 100%. The clinical
importance of this finding is not known.

Hydrochlorothiazide is rapidly
absorbed following oral administration. Onset of action of hydrochlorothiazide
is observed within one hour and persists for 6 to 12 hours. Hydrochlorothiazide
plasma concentrations attain peak levels at one to two hours and decline with a
half-life of four to five hours. Hydrochlorothiazide undergoes only slight
metabolic alteration and is excreted in urine. It is distributed throughout the
extracellular space, with essentially no tissue accumulation except in the
kidney.

Last reviewed on RxList: 3/21/2014
This monograph has been modified to include the generic and brand name in many instances.